Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism

ABSTRACT Microglia, the main resident immune cells of the brain, play critical roles in maintaining neuronal function and homeostasis. Microglia's metabolic flexibility enables rapid adaptation to environmental changes, yet the full extent of their metabolic capabilities and influence on neuronal metabolism remains unclear. While microglia predominantly rely on glucose oxidative metabolism under homeostatic conditions, they shift towards glycolysis upon proinflammatory activation. In this study, we investigated microglial metabolism and its impact on neuronal metabolic homeostasis using isotope tracing with stable carbon 13 C‐enriched substrates and gas chromatography–mass spectrometry (GC–MS) analysis. Primary microglia were incubated with 13 C‐labeled glucose, glutamine, or GABA in the presence or absence of lipopolysaccharide (LPS) to assess metabolic adaptations upon an inflammatory challenge. Additionally, neurons co‐cultured with quiescent or activated microglia (either with LPS or amyloid‐β) were incubated with 13 C‐enriched glucose to examine microglia–neuron metabolic interactions. Our findings confirm that microglia readily metabolize glucose and glutamine, with LPS stimulation slightly changing the glycolytic activity, as indicated by subtle changes in extracellular lactate. Importantly, we demonstrate for the first time that microglia take up and metabolize the inhibitory neurotransmitter GABA, suggesting a novel metabolic function. Furthermore, microglial presence directly influences neuronal metabolism and neurotransmitter homeostasis, highlighting a previously unrecognized aspect of neuron–microglia metabolic crosstalk. Collectively, these findings provide new insights into microglial metabolism and its role in neuronal function, with implications for neuroinflammatory and neurodegenerative diseases in which microglial metabolism is dysregulated. image